Abnormalities in brain serotonin concentration, high-affinity uptake, and tryptophan hydroxylase activity in severe-seizure genetically epilepsy-prone rats

Abstract

We characterized the nature of the deficit in brain serotonin (5-HT) exhibited by genetically epilepsy-prone rats (GEPR-9s) by regionally assessing three markers for 5-HT terminals/neurons (5-HT content, 5-HT uptake into the P2-synaptosomal fraction, and tryptophan hydroxylase activity) in GEPR-9s and nonepileptic control rats. As compared with controls, GEPR-9s had reduced brain 5-HT concentration, synaptosomal 5-HT uptake, and tryptophan hydroxylase activity (measured in vivo and in vitro) in most regions of the forebrain and in selected regions of brainstem. Analysis of kinetic constants for synaptosomal [(3)H]5-HT uptake and in vitro tryptophan hydroxylase activity showed that the decrements in these parameters exhibited by GEPR-9s resulted from reductions in V(max) rather than changes in K(m). In general, the reduction in each of the presynaptic markers for 5-HT terminals/neurons was similar in both magnitude and in their regional distribution in the GEPR-9 brain. An exception to this was noted in the midbrain tegmentum of GEPR-9s, which displayed a significant reduction in tryptophan hydroxylase activity without showing alterations in 5-HT concentration or in high-affinity 5-HT uptake. The present findings support the hypothesis that there is a widespread reduction in the number of serotonergic/neurons in GEPR-9 brain.